Drug's low solubility constitute a very difficult challenge to develop a bioavailable and physical stable pharmaceutical and nutraceutical product, particularly when intravenous or oral solutions are needed. A number of approaches for preparing intravenous and oral liquid compositions of sparingly or poorly water-soluble basic drugs are available. These methods include micellar solubilization or drug nanoparticle suspension by means of surface-active agents; formation of complexes with cyclodextrin and its derivatives (Hydroxypropyl beta-Cyclodextrin (HPBCD) and sulfobutylether-β-cyclodextrin (SBECD)); use of various co-solvent systems; and formation of salt with strong acid with a low solution pH. However, for micellar system, surfactants have been implicated by adverse effects such as irritation, hemolysis and histamine reaction and severe anaphylaxis reaction, and for nanosuspension system wherein pure drug particles of nanosize stabilized by polymer and surfactants, potential catalytic degradation of drug substance due to higher exposure area to aqueous media and the surrounding surfactants has been reported; taste masking and injection pain is another issue for the micellar/nanosuspension system due to a higher concentration of free drug available in the aqueous medium; co-solvent systems are known for causing precipitation, injection pain and phlebitis; potential nephrotoxicity and bradycardia and reduction of blood pressure caused by cyclodextrin and its derivatives and the potential concerns of cyclodextrin binding with co-administered lipophilic drugs have been reported; and the low solution pH of weakly basic salt formed with strong acid will cause drug-excipient and product stability issue and cause tasting issue, injection site irritation and pain as a result of precipitation of the drug as free base when contact with blood at neutral pH. In summary, each of these methods listed above has its inherent limitations and are insufficient to formulate low soluble drugs in a biocompatible vehicle having sufficient stability, minimum side effects, and appropriate pharmadynamic profiles as either intravenous, ocular, nasal, topical, transdermal, or oral administration.
Oil-in-water emulsions, which are made of oil droplets dispersed in an aqueous continuous phase, offers a unique system that can address drug solubility and stability problems with many applications in products such as pharmaceutical, food, and cosmetics. One of the uses of emulsions is to deliver active pharmaceutical ingredients and active components for use in topical, nutraceutical, oral, nasal, ocular, and pharmaceuticals. Active components that are soluble in oil can be dissolved/dispersed within the oil phase of the emulsion, and active components that are poorly soluble in both oil and water can be incorporated at the interfacial region of the emulsion as well.
Based on its appearance or particle size, emulsion can be classified into three types: macroemulsion, microemulsion and nanoemulsion. Macroemulsion with average size range of >100 nm tend to have a cloudy milky appearance because the many interfaces scatter light as it passes through the emulsion. Microemulsions and nanoemulsions, with average droplet sizes below 100 nm are two special classes of emulsions, appearing optically clear (translucent or transparent). This property is due to the fact that light are scattered by the droplets only if their sizes exceed about one-quarter of the wavelength of the incident light. When the mean droplet size in the emulsion is below about 100 nm, preferably below 70 nm, the light can penetrate through the emulsion without being scattered. Microemulsions are thermodynamic stable system, spontaneously formed by “solubilizing” oil molecules with a mixture of surfactants, co-surfactants, and co-solvents. Whereas nanoemulsion are thermodynamic metastable system, formation of which require external energy to break down oil droplet to below 100 nm level.
Conventional oil in water emulsions, i.e. macroemulsion, are inherently unstable system and will not form spontaneously. Energy input such as mechanical mixing, homogenizing, or ultrasound is required to form a macroemulsion; and macroemulsions tend to revert back to the stable state of the phases resulting phase separation such as agglomeration and creaming. Besides physical instability, relative large droplet size of macroemulsions have a lower interfacial area to volume ratio that limit the ability of macroemulsion to efficiently dissolve poorly soluble compounds, which are soluble either inside oil or at the oil-water interface; and the opacity of macroemulsion reduce visual clarity when administration to eyes. Furthermore, the release of the active ingredient from macroemulsions comprised of long chain triglyceride oil by oral administration maybe be often limited by the rate and extent of lipolysis. The rate of triglyceride emulsion digestion in GI tract is a function of pH, lipase concentration, bile salt and emulsion surface area. Emulsions with higher surface area to volume ratios would undergo faster lipolysis than those with low surface area to volume ratios.
Formulations of emulsion into average size below 100 nm are exceptions to those disadvantages, wherein microemulsions are thermodynamically stable, and nanoemulsions, though thermodynamically metastable in nature, could still maintain its kinetic stability for a long time period due to extremely small size. The formation of emulsions below 100 nm has added benefits of increasing the relative amount of interfacial area considerably. An increase in the relative amount of interfacial area can lead to a greater ability to dissolve poorly soluble active components into the aqueous medium and a faster rate of digestion by lipolysis as compared to macro emulsions and thus a faster release of the active ingredient from the oil droplets. Due to small size below 100 nm, microemulsion or nanoemulsion has added benefit of aiding active compounds to penetrate epithelial mucosal layers such as eyes, skin, nasal, lung, GI tract, tumor, blood vein, and blood-brain barrier.
Despite of the similarity in particle size less than 100 nm and performance in delivery of active compounds, microemulsions and nanoemulsions are fundamentally different. Despite of its thermodynamic stability, the required surfactant concentration for a microemulsion system significantly exceeds the concentration of the oil phase and is normally several times higher than that of nanoemulsion. Because of many undesirable side-effects caused by surfactants and due to the government regulations of daily intake limits of many surfactants, microemulsions are disadvantageous in many pharmaceutical applications such as intravenous, ocular, and oral administration as compared to nanoemulsions. In addition, many surfactants have a bitter taste when present in the foods/dosage form, which may cause palatability issues. Furthermore, the physical stability of a microemulsion system is often affected by dilution, by heating, or by changing pH levels.
A nanoemulsion—even though it will not be formed spontaneously and only maintain a kinetic stability—uses much less surfactant due to the aid of mechanic shear to break down oil droplets to nanosize level in the presence of water and surfactant. This leads to a more tolerable system from a toxicological and regulatory perspective. Similarly as microemulsions, nanoemulsions can have the benefit of appearing translucent as a result of their small size. Nanoemulsions have the same high interfacial area to volume ratio as microemulsions, which can aid in the dissolution of poorly soluble compounds and aid in the rapid digestion of the emulsion by lipolysis. In contrast to microemulsions, nanoemulsions maintain its physical stability upon dilution and/or change in pH.
Despite of many advantages over macroemulsion and microemulsions, nanoemulsions have its limitations, i.e. kinetic stability—the particle size may increase over time via Ostwald ripening. An increase in nanoemulsion particle size over time is disadvantageous as the nanoemulsion will lose its clarity accompanied with a corresponding decrease in interface surface area. In order to achieve stable nanoemulsion with average particle size below 100 nm, low viscosity oils including short chain triglycerides or medium chain triglycerides such as Migloyol are often utilized to make nanoemulsion, the disadvantage of which is the tendency of Ostwald ripening due to smaller molecular size, high aqueous solubility and low viscosity of short/medium chain triglycerides. To improve physical stability of nanoemulsion, long chain triglycerides with very low aqueous solubility may be employed. However, it is known that the large molecular volume and high viscosity of long chain triglycerides prevents them from readily forming optically clear (transparent or translucent) nanoemulsions with a high level of oil content. Therefore, in order to form translucent nanoemulsion comprising long chain triglyceride, either high level of small molecule weight organic cosolvent such as alcohol, or higher levels of toxic surfactants such as Cremophor EL relative to that of oil phase, are commonly utilized to reduce the surface tension of the oil droplets comprising long chain triglyceride. This, however may lead to an intolerable system from safety, toxicological, regulatory perspective. For example, since phosphatidylcholines (egg or soy lecithin) are naturally occurring non-toxic, biocompatible surfactants, the preparation of lecithin-based emulsions is of considerable pharmaceutical interest. However, since lecithin has a strong tendency to form liquid crystalline structures at a relatively low concentration, particularly in water phase, adding alcohol to the aqueous phase as a cosolvent is necessary in order to reduce the interfacial tension thus to produce lecithin-based microemulsion/nanoemulsion comprising long chain triglyceride oils. However, alcohol is known to induce toxic side effects such as enzyme induction, drug-drug interaction, or damage to central nerve system.
Therefore, challenges remain in creating nanoemulsion with its oil phase comprising long chain triglyceride with a high level of oil content of the composition, wherein the emulsion has an average size of less than 100 nm (intensity averaged), maintains good stability against Ostwald ripening and optical translucency, uses biocompatible surfactant and relative low level of other surfactants, and eliminate the use of undesirable alcohol as co-solvent in the aqueous phase. The creation of such nanoemulsions would have advantages in improving emulsion product safety, efficacy, stability, tolerability, and taste.